U.S. patent number 4,690,930 [Application Number 06/795,168] was granted by the patent office on 1987-09-01 for pyrazolo[4,3-c]quinoline-3-one and imidazo[4,3-c]cinnolin-3-one derivatives and their use as psychotropic agents.
This patent grant is currently assigned to Shionogi & Co., Ltd. Invention is credited to Masami Eigyo, Akira Matsushita, Takashi Sasatani, Hirohisa Shindo, Susumu Takada.
United States Patent |
4,690,930 |
Takada , et al. |
September 1, 1987 |
Pyrazolo[4,3-c]quinoline-3-one and imidazo[4,3-c]cinnolin-3-one
derivatives and their use as psychotropic agents
Abstract
Compounds of the formula (I): ##STR1## wherein R.sup.1 and
R.sup.2 each is hydrogen, alkyl, alkoxycarbonyl, carboxy, halogen,
nitro or trifluoromethyl, or R.sup.1 and R.sup.2 taken together may
form alkylene; R.sup.3 is hydrogen, alkyl, alkanoyl or
alkylsulfonyl; R.sup.4 is hydrogen, alkoxycarbonyl, carboxy or
halogen; X is hydrogen, alkyl, alkoxy, halogen or hydroxy; and Y is
methine or nitrogen or salts thereof are provided. The compounds
(I) show potent psychotropic activity.
Inventors: |
Takada; Susumu (Hyogo,
JP), Sasatani; Takashi (Nara, JP), Shindo;
Hirohisa (Osaka, JP), Matsushita; Akira (Hyogo,
JP), Eigyo; Masami (Nara, JP) |
Assignee: |
Shionogi & Co., Ltd (Osaka,
JP)
|
Family
ID: |
16956169 |
Appl.
No.: |
06/795,168 |
Filed: |
November 5, 1985 |
Foreign Application Priority Data
|
|
|
|
|
Nov 5, 1984 [JP] |
|
|
59-233511 |
|
Current U.S.
Class: |
514/293; 514/248;
544/234; 546/82 |
Current CPC
Class: |
A61P
25/20 (20180101); A61P 25/24 (20180101); C07D
487/04 (20130101); C07D 471/04 (20130101); A61P
25/26 (20180101); A61P 25/18 (20180101); A61P
25/08 (20180101); C07D 409/12 (20130101); A61P
25/00 (20180101); C07D 333/36 (20130101) |
Current International
Class: |
C07D
409/00 (20060101); C07D 409/12 (20060101); C07D
333/00 (20060101); C07D 471/04 (20060101); C07D
471/00 (20060101); C07D 333/36 (20060101); C07D
487/04 (20060101); C07D 487/00 (20060101); A61K
031/415 (); C07D 471/04 (); C07D 237/28 () |
Field of
Search: |
;546/82 ;544/234
;514/293,248 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
Other References
Fryer et al., Life Sciences, vol. 39, pp. 1947-1957, (1986). .
Goodnick et al., J. Clin. Psychiatry 45; 5 May 1984. .
File, S. E., Neuroscience Letters, 35, (1983), 317-320. .
Peterson, E. N., European J. of Pharmacology 94, (1983), 117-124.
.
Ghoneim et al., Psychopharmacology, (1977). .
Block et al., Experimental Aging Research, vol. II, No. 3, fall
1985. .
Tamminga et al., The Lancet, Jul. 9, 1983, pp. 98-99. .
Braestnip et al., Bioch. Pharm., vol. 33, No. 6, pp. 859-862,
(1984). .
Jensen et al., Psychopharmacology, 64, (1979). .
Yenault et al., Nature, vol. 321, 26 Jun. 1986. .
Katrizky et al, Comprehensive Heterocyclic Chemistry, vol. 4, p.
810, (1984), Pergamon Press. .
B von M. Hentschel et al., J. prakt. Chem., 316, 878-880, (1974).
.
Huddleston et al, J. Chem. Research (S), 1980, 238-239..
|
Primary Examiner: Ford; John M.
Assistant Examiner: Richter; J.
Attorney, Agent or Firm: Birch, Stewart, Kolasch &
Birch
Claims
What we claim is:
1. A compound of the formula: ##STR48## wherein R.sup.1 and R.sup.2
each is hydrogen, C.sub.1 --C.sub.5 alkyl, halogen, nitro or
trifluoromethyl, or R.sup.1 and R.sup.2 taken together may form
C.sub.3 -C.sub.4 alkylene; R.sup.3 is hydrogen, C.sub.1 -C.sub.5
alkyl, C.sub.1 -C.sub.5 alkanoyl or C.sub.1 -C.sub.5 alkylsulfonyl;
X is hydrogen, C.sub.1 -C.sub.5 alkyl, C.sub.1 -C.sub.5 alkoxy,
halogen or hydroxy; and Y is methine or nitrogen or a salt
thereof.
2. The compound of claim 1, wherein Y is methane.
3. The compound of claim 1, wherein R.sup.1 and R.sup.2 each is
hydrogen or C.sub.1 -C.sub.5 alkyl.
4. The compound of claim 1, wherein X is hydrogen, C.sub.1 -C.sub.5
alkyl, C.sub.1 -C.sub.5 alkoxy or halogen.
5. The compound of claim 1, wherein R.sup.1 and R.sup.2 each is
hydrogen or C.sub.1 -C.sub.5 alkyl; R.sup.3 is hydrogen; X is
hydrogen or C.sub.1 -C.sub.5 alkyl; and Y is methine.
6. The compound of claim 1, which is an organic acid addition salt
of said compound of the formula (I).
7. The compound of claim 1, which is an inorganic acid addition
salt of said compound of the formula (I).
8. The compound of claim 1, which is an alkali metal salt of said
compound of the formula (I).
9. A pharmaceutical composition comprising:
a psychotropically effective amount of a compound of the formula:
##STR49## wherein R.sup.1 and R.sup.3 each is hydrogen, C.sub.1
-C.sub.5 alkyl, halogen, nitro or trifluoromethyl, or R.sup.1 and
R.sup.2 taken together may form C.sub.3 -C.sub.4 alkylene; R.sup.3
is hydrogen, C.sub.1 -C.sub.5 alkyl, C.sub.1 -C.sub.5 alkanoyl or
C.sub.1 -C.sub.5 alkylsulfonyl; X is hydrogen, C.sub.1 -C.sub.5
alkyl, C.sub.1 -C.sub.5 alkoxy, halogen or hydroxy; and Y is
methine or nitrogen; or a pharmaceutically acceptable salt thereof
in admixture with
a pharmaceutically acceptable diluent.
10. The composition of claim 9, in the form of a tablet.
11. The composition of claim 9, in the form of a pill.
12. A method for treating psychotropic disorders which comprises
administering to a patient an effective amount of a pharmaceutical
composition comprising:
a psychotropically effective amount of a compound of the formula:
##STR50## wherein R.sup.1 and R.sup.2 each is hydrogen, C.sub.1
-C.sub.5 alkyl, halogen, nitro or trifluoromethyl, or R.sup.1 and
R.sup.2 taken together may form C.sub.3 -C.sub.4 alkylene; R.sup.3
is hydrogen, C.sub.1 -C.sub.5 alkyl, C.sub.1 -C.sub.5 alkanoyl or
C.sub.1 -C.sub.5 alkylsulfonyl; X is hydrogen, C.sub.1 -C.sub.5
alkyl, C.sub.1 -C.sub.5 alkoxy, halogen or hydroxy; and Y is
methine or nitrogen; or a pharmaceutically acceptable salt thereof
admixture with
a pharmaceutically acceptable diluent.
13. The method of claim 12, wherein said compound of the formula
(I) is administered in an amount of 0.1 to 500 mg per day.
Description
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to thienyl condensed pyrazole
derivatives which show potent psychotropic activity.
2. Prior Art
2-Phenylpyrazolo[4,3-c]quinolin-3-one derivatives have an affinity
to benzodiazepine receptor and are known as useful psychotropic
agents such as antidepressant and tranquilizer [U.S. Pat. No.
4,312,870]. Furthermore, it is known that
2-thiazolylpyrazolo[4,3-c]quinolin-3-one derivatives have the same
utility as said derivatives [U.S. Pat. No. 4,524,146], but
thienyl-substituted compounds of the latter are not disclosed
illustratively.
BRIEF SUMMARY OF THE INVENTION
The present invention relates to compounds of the formula (I):
##STR2## (wherein R.sup.1 and R.sup.2 each is hydrogen, alkyl,
alkoxycarbonyl, carboxy, halogen, nitro or trifluoromethyl, or
R.sup.1 and R.sup.2 taken together may form alkylene; R.sup.3 is
hydrogen, alkyl, alkanoyl or alkylsulfonyl; R.sup.4 is hydrogen,
alkoxycarbonyl, carboxy or halogen; X is hydrogen, alkyl, alkoxy,
halogen or hydroxy; and Y is methine or nitrogen) or salts
thereof.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to the compounds of the formula (I):
##STR3## (wherein R.sup.1 and R.sup.2 each is hydrogen, alkyl,
alkoxycarbonyl, carboxy, halogen, nitro or trifluoromethyl, or
R.sup.1 and R.sup.2 taken together may form alkylene; R.sup.3 is
hydrogen, alkyl, alkanoyl or alkylsulfonyl; R.sup.4 is hydrogen,
alkoxycarbonyl, carboxy or halogen; X is hydrogen, alkyl, alkoxy,
halogen or hydroxy; and Y is methine or nitrogen) or salts
thereof.
The compounds (I) of the present invention are useful as
psychotropic agents.
The compounds (I) can be prepared according to Methods A, B, and/or
C. ##STR4## (wherein A is a leaving group; Hal is halogen; R is
alkyl; and R.sup.1, R.sup.2, X, and Y each has the same meaning as
defined above).
Steps 1 to 5 each will be explained below.
Step 1
The compound (Ia) is prepared by cyclization of the starting
material (II) in this step. This reaction can be carried out in a
solvent such as alkanols (e.g. methanol, ethanol, isopropanol,
etc.), halogenohydrocarbons (e.g. dichloromethane, dichloroethane,
chloroform, carbon tetrachloride, etc), aromatic solvents (e.g.
benzene, toluene, xylene, etc.), or dimethylformamide; at a
temperature of about 10.degree..about.about 100.degree. C., if
required in the presence of an inorganic base such as alkali
hydroxide (e.g. potassium hydroxide, sodium hydroxide, lithium
hydroxide, etc.), alkali carbonate (e.g. potassium carbonate,
sodium carbonate, etc.), alkali bicarbonate (e.g potassium
bicarbonate, sodium bicarbonate, etc.), and the like; an organic
base such as triethylamine, pyridine, picoline, quinoline,
piperidine, pyrrolidine, N-methylmorpholine, and the like; an
inorganic acid such as hydrochloric acid, sulfuric acid, phosphoric
acid, and the like; and an organic acid such as acetic acid,
trifluoroacetic acid, toluenesulfonic acid, and the like.
The base or acid may be selected in accordance with the properties
of the substituents on the thieny group of the starting material
(II) and the properties of the leaving group A. The reaction is
preferably carried out at a temperature of about
10.degree..about.about 30.degree. C., if a base or an acid is
used.
The reaction may be accelerated under inert gas flow such as
nitrogen, argon, etc.
The starting material (II) is, for example, provided according to
the following method. ##STR5## (wherein A, R, R.sup.1, R.sup.2, X,
and Y each has the same meaning as defined above).
Step 2
The compound (Ia) is hydrolyzed to give the compound (Ib) in this
step. The reaction can be conducted in a conventional manner of
hydrolysis. For example, the reaction can be carried out by
treating the compound (Ia) with an inorganic base in a solvent. As
the solvent, water; alkanols (e.g. methanol, ethanol, isopropanol,
etc.); halogenohydrocarbons (e.g. dichloromethane, dichloroethane,
chloroform, carbon tetrachloride, etc.); ethers (e.g. ether,
tetrahydrofuran, dioxane, etc.); dimethylformamide;
dimethylsulfoxide, and the like or the mixture thereof may be used.
As the inorganic base, alkali hydroxide, alkali carbonate, alkali
bicarbonate, and the like may be employed. The reaction is
performed at a temperature of about 30.degree..about.about
120.degree. C., preferably, about 50.degree..about.about 80.degree.
C. under inert gas flow such as nitrogen or argon in the same
manner as in Step 1. Step 2 can be carried out continuously after
Step 1.
Step 3
The decarboxylation of the thiophene carboxylic acid (Ib) is
perfomed in an organic solvent such as quinoline, isoquinoline, and
the like. at a temperature of about 150.degree..about.about
250.degree. C., if necessary, in the presence of a catalyst such as
copper powder, chromous acid-copper (CuO.Cr.sub.2 O.sub.3),
etc.
The reaction can also be achieved as follows. Thus, the compound
(Ib) is converted into its alkali metal salt by treating with
alkali hydroxide, and then the alkali metal salt of Ib is heated at
about 150.degree..about.about 250.degree. C. in the presence of a
base (e.g. calcium oxide-sodium hydroxide etc.)
Step 4
The objective compound (Id) is prepared by introduction of an
alkanoyl to the compound (Ic) or alkylation of Ic. The reaction is
conducted with an alkylating agent or alkanoyl indroducing agent in
an appropriate solvent in the presence of an alkali hydride such as
sodium hydride, potassium hydride, and the like. The reaction is
carried out at a temperature of 30.degree..about.120.degree. C. As
the alkylating agent, alkyl halide (e.g. methyl bromide, ethyl
iodide, propyl chloride, etc.), dialkyl sulfate (e.g. dimethyl
sulfate, diethyl sulfate, etc.), and the like may be used. As the
alkanoyl introducing agent, alkanoyl halide (e.g. acetyl chloride,
butyryl bromide, etc.) or alkanoic acid anhydride (e.g. acetic
anhydride, propionic anhydride) can be used. As the solvent,
tetrahydrofuran, dioxane, diglyme, dimethylformamide, and the like
are preferred.
Step 5
The compound (Ie) is prepared by halogenation of the compound (Ic).
The halogenation can be performed by reacting the compound (Ic)
with halogen such as fluorine, chlorine, bromine, iodine, etc. in
an appropriate solvent in a conventional manner. As the solvent,
halogenohydrocarbons such as dichlormethane, dichloroethane,
chloroform, carbon tetrachloride, and the like may be employed. The
reaction is accomplished at a temperature of room temperature to
refluxing temperature within a period of several hours to several
tens hours.
The halogenation can also be achieved by using N-bromosuccinimide,
N-chlorosuccinimide, sulfuryl chloride, and the like.
The compound (Ic) may be also prepared according to the following
Method B. ##STR6## (wherein A, R.sup.1, R.sup.2, X, and Y each has
the same meaning as defined above; R.sup.5 is alkoxycarbonyl,
acetyl, or trifluoroacetyl, etc.)
Method B is carried out by reacting the compound (V) with an acid
at a temperature of room temperature to about 100.degree. C. in an
appropriate solvent, if required by addition of a base. As the
acid, strong acid such as trifluoroacetic acid, hydrobromic
acid-acetic acid may preferably be used. The base may be selected
suitably from the group consisting of inorganic bases such as
alkali hydroxide (e.g. potassium hydroxide, sodium hydroxide,
lithium hydroxide, etc.); alkali carbonate (e.g. potassium
carbonate, sodium carbonate, etc.); alkali bicarbonate (e.g.
potassium bicarbonate, sodium bicarbonate, etc.); organic base such
as triethylamine, pyridine, picoline, quinoline, piperidine,
pyrrolidine, N-methylmorpholine, and the like. The solvent used in
the reaction is exemplified by alkanols (e.g. methanol, ethanol,
isopropanol, etc.); halogenohydrocarbons (e.g. dichloromethane,
dichloroethane, chloroform, carbon tetrachloride, etc.); ethers
(e.g. dibutyl ether, tetrahydrofuran, etc.), and the like.
The reaction is accomplished over a period of several tens minutes
to several hours, by which the compound (Ic) is produced.
The compound (Id) and the compound (Ie) are prepared from the
compound (Ic) in the same manner as in Steps 4 and 5 respectively
in Method A.
The objective compound (I) wherein R.sup.1 is hydrogen can be
prepared by the following Method C. ##STR7## (wherein A, R.sup.2,
R.sup.4, X, and Y each has the same meaning as defined above; R' is
alkyl).
Steps 1 to 3 can be conducted as follows.
Step 1
The compound (IV') in which the thiophene is protected at the 2
position is used in this step. For example, the compound (IV')
protected by alkoxycaronyl (R'OCO--) or an acid addition salt such
as hydrochloride of the compound (IV') is allowed to react with the
compound (III) in an appropriate solvent at a temperature of about
10.degree..about.about 100.degree. C., if required by addition of a
base or an acid. The solvent includes alkanols (e.g. methanol,
ethanol, isopropanol, etc.); halogenohydrocarbons (e.g.
dichlorometahne, dichloroethane, chloroform, carbon tetrachloride,
etc.); aromatic solvents (e.g. benzene, toluene, xylene, etc.);
dimethylformamide, and the like. As the base, inorganic bases such
as alkali hydroxide, alkali carbonate, alkali bicarbonate, and the
like; organic bases such as triethylamine, pyridine, picoline,
quinoline, piperidine, pyrrolidine, N-methylmorpholine, and the
like may be used. As the acid, inorganic acids such as hydrochloric
acid, sulfuric acid, phosphoric acid, and the like, and organic
acids such as acetic acid, trifluoroacetic acid, toluenesulfonic
acid, and the like can be employed.
In this step it seemed that the compound (IV) would be produced as
an intermediate, while the cyclized compound (If) has been directly
provided.
Step 2
The compound (Ig) is prepared by hydrolysis of the compound (If) in
this step.
In this step, the reaction may be conducted in the same manner as
in Step 2 of Method A. This reaction may be conducted in a
conventional manner for hydrolysis, for example, it is carried out
by treating with an inorganic base in an appropriate solvent.
The solvent includes water; alkanols (e.g. methanol, ethanol,
isopropanol, etc.); halogenohydrocarbons (e.g. dichloromethane,
dichloroethane, chloroform, carbon tetrachloride, etc.); ethers
(e.g. ether, tetrahydrofuran, dioxane, etc.); dimethylformamide;
dimethylsulfoxide, and a mixture thereof. As the inorganic base,
alkali hydroxide, alkali carbonate, alkali bicarbonate, and the
like may be employed. The reaction may be carried out at a
temperature of about 30.degree. to about 120.degree. C.,
preferably, about 50.degree. to about 80.degree. C., under inert
gas flow such as nitrogen, argon, and so on.
Step 3
The compound (Ih) can be prepared by decarboxylation of the
compound (Ig) in this step; the reaction may be carried out in the
same manner as in Step 3 of Method A.
The reaction can be carried out in a solvent such as quinoline,
isoquinoline, etc. at a temperature of about 150.degree. to about
250.degree. C., if necessary, in the presence of a catalyst such as
copper powder, chromous acid-copper (CuO.Cr.sub.2 O.sub.3),
etc.
The reaction can also be achieved as follows. Thus, the compound
(Ig) is converted into its alkali metal salt by treating with
alkali hydroxide, and then the alkali metal salt of Ig is heated at
about 150.degree. to about 250.degree. C. in the presence of a base
(e.g. calcium oxide-sodium hydroxide etc.)
In Method C, Steps 1 to 3 can be carried out continuously, or the
product in each step can be isolated.
The compound (Ih) can be subjected to alkylation or introduction of
alkanoyl in the same manner as in Step 4 of Method A. The compound
(Ih) can be halogenized in the same manner as in Step 5 in Method
A.
The objective compound (I) can also be prepared by cyclizing a
4-[2(3)-thienylhydrazono]-3-carboxylic acid ester. The ester is
provided from the compound in which the substituent on the
thiophene of the corresponding compound (IV) or (IV') (i.e.
alkoxycarbonyl ROCO--, R'OCO--) is replaced by an
electron-withdrawing group such as nitro.
The terms used in the above definitions are illustratively
explained below.
The alkyl includes C.sub.1 -C.sub.5 alkyl such as methyl, ethyl,
n-propyl, isopropyl, n-butyl, tert-butyl, n-pentyl, isopentyl, and
the like.
The alkoxy includes C.sub.1 -C.sub.5 alkoxy, for example, methoxy,
ethoxy, n-propoxy, isopropoxy, butoxy, pentyloxy, and the like.
The alkanoyl is exemplified by C.sub.1 -C.sub.5 alkanoyl, such as
formyl, acetyl, propionyl, butryl, valeryl, and the like.
The alkoxycarbonyl includes C.sub.2 -C.sub.5 alkoxycarbonyl such as
methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl,
isopropoxycarbonyl, n-butoxycarbonyl, sec-butoxycarbonyl,
tert-butoxycarbonyl, and the like.
The alkylene is exemplified by C.sub.3 -C.sub.4 alkylene such as
trimethylene and tetramethylene.
The alkylsulfonyl includes C.sub.1 -C.sub.5 alkylsulfonyl such as
methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl,
n-butylsulfonyl, tert-butylsulfonyl, n-pentylsulfonyl,
isopentylsulfonyl, and the like.
The halogen includes fluorine, chlorine, bromine, iodine, and the
like.
As the representatives of the leaving group are alkoxy such as
methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy,
sec-butoxy, and tert-butoxy. The objective compounds (I) can be
converted into inoganic aor organic acid addition salt thereof, if
required. The inorganic acid includes hydrochloric acid,
hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and
the like; the organic acid includes acetic acid, methanesulfonic
acid, succinic acid, maleic acid, tartaric acid, benzoic acid, and
the like.
The compounds (I) can be converted into alkali metal salt thereof
such as sodium, potassium, or lithium salt thereof.
The objective compound (I) wherein R.sup.3 is hydrogen can be exist
as a tautomer. ##STR8## (wherein R.sup.1, R.sup.2, R.sup.4, X, and
Y each has the same meaning as defined above).
The objective compounds (I) or salts thereof have a high affinity
to a benzodiazepine-receptor, and they are useful as psychotropic
agents such as minor tranquilizers, anticonvulsants, agents for
treating benzodiazepine intoxidation, or activators of
mentation.
The compound of the present invention can be administered orally or
parenterally to human beings or other mammals.
The compound of the present invention can be formulated as tablets,
capsules, pills, granules, injections, suppositories, and syrups in
a conventional manner. As pharmaceutically acceptable diluents,
lactose, sucrose, wheat starch, potato starch, magnesium stearate,
gelatin, methyl cellose, agar, water and the like can be used. If
required, stabilizers, emulsifiers, buffers, and other additives
can be added.
The compounds (I) can be administered orally at a dose or doses of
0.1.about.500 mg per day.
The present invention will be explained in more detail by the
following Examples, Referential Examples, and Preparations.
The abbreviations used in Examples, Referetial Examples, and Tables
each has the following meanings.
Me: methyl; Et: ethyl; Bu:butyl; (d): decomposition point
EXAMPLE 1
(1)
2-[2-(3-Ethoxycarbonyl-5-methylthienyl)]-2,5-dihydro-3H-pyrazolo[4,3-c]qui
nolin-3-one Ia.sub.1 -1 ##STR9##
To a suspension of 1.04 g of ethyl
4-[2-(3-ethoxycarbonyl-5-methylthienyl)hydorazono]-1,4-dihydroquinoline-3-
carboxylate II.sub.1 -1 in 15 ml of ethanol is added 4 ml of 1N
sodium hydroxide under nitrogen gas at room temperature. The
mixture is stirred for 30 minutes, acidified with acetic acid, and
dried up under reduced pressure. The residue is mixed with water,
filtered, and washed with water and ethanol. The resulting solid is
crystallized from chloroform-ethyl acetate to give 1.17 g of
yellowish crystalline Ia.sub.1 -1. This is recrystallized from
chloroform-ethyl acetate to give yellowish crystals, melting at
248.degree..about.250.degree. C. (d).
(2)
2-[2-(3-Carboxy-5-methylthienyl)]-2,5-dihydro-3H-pyrazolo[4.3-c]quinolin-3
-one Ib.sub.1 1 ##STR10##
To a suspension of 707 mg of
2-[2-(3-ethoxycarbonyl-5-methylthienyl)]-2,5-dihydro-3H-pyrazolo[4,3-c]qui
nolin-3-one Ia.sub.1 -1 in 10 ml of methanol is added 10 ml of 1N
sodium hydroxide. The mixture is stirred at 60.degree. C. for 1
hour, cooled, neutralized with 10 ml of 1N hydrochloric acid, and
acidified with acetic acid. The precipitating crystalline material
is collected by filtration, washed with ater, and dried to give 637
mg of yellowish crystalline Ib.sub.1 -1. m.p.:
300.degree.-303.degree. C. (d).
Ib.sub.1 -1 can be directly provided from IIb.sub.1 -1 in the same
treatment as in the above description.
EXAMPLES 2-13 ##STR11##
To a suspension of an ethyl
4-[2-(3-alkoxycarbonylthienyl)-hydrazono]-1,4-dihydroquinoline-3-carboxyla
te (II.sub.1) in ethanol is added aqueous 1N sodium hydroxide under
nitrogen gas at room temperature. The mixture is stirred for about
several 10 minutes to about several hours, acidified with acetic
acid, and dried up under reduced pressure. The residue is washed
with water and ethanol in order. The reslting solid is crystallized
from chloroform-ethyl acetate to give yellow crystalline Compound
(Ia.sub.1). ##STR12##
To a suspension of a
2-[2-(3-alkoxycarbonylthienyl)]-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-o
ne (Ia.sub.1) in methanol is added aqueous 1N sodium hydroxide
under nitrogen gas. The mixture is stirred under heating for about
several 10 minutes to about several hours. After cooling, the
mixture is neutralized with 1N hydrochloric acid and acidified with
acetic acid. The precipitating crystals are collected by
filtration, washed with water, and dried to give a
2-[2-(3-carboxythienyl)]-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one
(Ib.sub.1).
The reaction conditions to prepare Compound (Ia.sub.1) from
corresponding Compound (II.sub.1), yield (g), (%), structural
formulae, recrystallization solvent, and melting point relative to
the compound (Ia.sub.1) are summarized in Table 1.
The reaction conditions to prepare Compound (Ib.sub.1) from
corresponding Compound (Ia.sub.1), yield (g), (%), structural
formulae, appearance, and decomposition point of the compound
(Ib.sub.1) are shown in Table 2.
TABLE 1 ##STR13## reaction Compound (Ia.sub.1) Ex. Amount of
Compound ethanol 1NNaOH time yield yield Compd. crystal
recrystallization m.p. No. (II.sub.1) (g) (ml) (ml) (hrs) (g) (%)
No. R.sup.1 R.sup.2 R X water solvent (.degree.C.) 2 0.82 10 2.2
0.5 0.66 90 Ia.sub. 1 -2 Et H Et H 1/4 H.sub.2 O CHCl.sub.3EtOAc
175-178 3 0.92 8 2.5 1 0.52 66 Ia.sub.1 -3 Me Me Et H --
CHCl.sub.3MeOH 252-253 4 0.63 7 1.6 0.8 0.475 88 Ia.sub.1 -4
(CH.sub.2).sub.4 Et H -- CHCl.sub.3 MeOH 281-284 5 2.14 70 10 1
1.80 93 Ia.sub.1 -5 n-Bu H Et H -- n-hexane-EtOH 210-212 6 1.04 20
2.9 1 0.88 96 Ia.sub.1 -6 Me H Me 8-Me H.sub.2 O MeOH 162-164d 7
1.15 50 3.4 1 0.93 91 Ia.sub.1 -7 Me H Me 8-MeO -- MeOH 255-259 8
0.98 20 2.6 1.5 0.80 92 Ia.sub.1 -8 Me H Me 8-Cl H.sub.2 O MeOH
166-169 9 1.05 20 2.9 1 0.865 93 Ia.sub.1 -9 Me H Me 8-F 1/5
H.sub.2 O MeOHbenzene 168-171 10 0.70 5 1.9 1 0.55 88 Ia.sub.1 -10
Me H Me 7-Me -- EtOH 246--248 11 1.67 100 8.0 1 1.36 93 Ia.sub.1
-11 Me H Me 7-Cl -- EtOH 261-263 12 0.472 5 1.2 0.7 0.386 90
Ia.sub.1 -12 COOEt Me Et H -- CHCl.sub.3EtOH 282-285 13 2.36 50 6.6
0.5 1.99 94 Ia.sub.1 -13 H COOEt Et H 1/3 H.sub.2 O MeOH
255-258
TABLE 2 ##STR14## reaction reaction Compound (Ib.sub.1) Ex. Amount
of Compound methanol 1 NNaOH temperature time yield yield Compd
crystal dec. point No. (Ia.sub.1) (g) (ml) (ml) (.degree.C.) (hrs)
(g) (%) No. R.sup.1 R.sup.2 X water appearance (.degree.C.) 2 0.558
10 10 40 1.5 0.481 92 Ib.sub.1 -2 Et H H 1/2 H.sub.2 O yellow 2
80-283 3 0.500 5 10 reflux 2 0.35 76 Ib.sub.1 -3 Me Me H 1/2
H.sub.2 O yellow 289-291 4 0.48 5 8 reflux 2 0.429 96 Ib.sub.1 -4
(CH.sub.2).sub.4 H 1/2 H.sub.2 O yellow 294-296 5 0.70 10 5.4
reflux 0.5 0.630 95 Ib.sub.1 -5 n-Bu H H 1/2 H.sub.2 O yellow
280-281 6 0.82 8 10 60 0.5 0.716 91 Ib.sub.1 -6 Me H 8-Me 1/5
H.sub.2 O yellow 293-294.5 7 0.88 13 7.2 reflux 0.5 0.710 84
Ib.sub.1 -7 Me H 8-MeO 2/5 H.sub.2 O yellow 295-2963 8 0.73 7 10 60
0.5 0.672 96 Ib.sub.1 -8 Me H 8-Cl H.sub.2 O yellow 12-314 9 0.79 8
10 60 0.6 0.683 86 Ib.sub.1 -9 Me H 8-F 3/5 H.sub.2 O yellow
299-301 10 0.436 8 4 reflux 0.5 0.375 86 Ib.sub.1 -10 Me H 7-Me 1/2
H.sub.2 O yellowish- 308-311 green 11 1.19 18 9.6 reflux 0.5 1.10
95 Ib.sub.1 -11 Me H 7-Cl 1/2 H.sub.2 O yellowish- 316-317 green 12
0.638 15 15 70 1.5 0.541 98 Ib.sub.1 -12 COOH Me H 3/5 H.sub.2 O
yellowish- 248-251 green 13 0.350 5 5 60 1.5 0.229 75 Ib.sub.1 -13
Cl COOH H 1/2 H.sub.2 *Ib.sub.1 -13 is prepared from Ia.sub.1 -13'
which is produced in Example 58.
EXAMPLE 14
2-[2-(5-Methylthienyl)]-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one
Ic.sub.1 -1 ##STR15##
To a suspension of 390 mg of
2-[2-(3-carboxy-5-methylthienyl)]-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3
-one Ib.sub.1 -1 in 6 ml of quinoline is added 150 mg of copper
powder. The mixture is stirred under nitrogen gas at 200.degree. C.
for 45 minutes. After cooling, copper powder is removed by
filtration, and the filtrate is mixed with 1N sodium hydroxide and
shaken with ether. The separated aqueous layer is filtered; and the
filtrate is mixed with acetic acid. The precipitating crystals are
collected by filtration and recrystallized from ethanol to give 280
mg of Ic.sub.1 -1 as yellow crystals.
m.p.: 309.degree.-311.degree. C. (d).
EXAMPLES 15-26 ##STR16##
To a suspension of the compound (Ib.sub.1) in quinoline is added
copper powder. The mixture is stirred at a temperature of heating
under nitrogen gas for several 10 minutes to several hours. After
cooling, copper powder is removed by filtration, and the filtrate
is mixed with 1N sodium hydroxide and shaken with ether. The
separated aqueous layer is filtered; and the filtrate mixed with
acetic acid. The precipitating crystalline material is collected by
filtration and crystallized from an appropriate solvent to give the
compound (Ic.sub.1). The reaction conditiions to prepare the
compound (Ic.sub.1) from the compound (Ib.sub.1); yield (g), (%),
structural formulae, recrystallization solvent, and decomposition
point of the compound (Ic.sub.1) are shown in Table 3.
TABLE 3
__________________________________________________________________________
##STR17## Amount reaction reac- Compound (Ic.sub.1) of Com- quino-
copper temper- tion recrystal- dec. Ex. pound line pow- ature time
yield yield Compd. crystal lization point No. (Ib.sub.1) (g) (ml)
der (g) (.degree.C.) (min) (mg) (%) No. R.sup.1 R.sup.2 X water
solvent (.degree.C.)
__________________________________________________________________________
15 0.348 6 0.15 195 90 273 91 Ic.sub.1 -2 Et H H 1/4 H.sub.2 O EtOH
277-280 16 0.339 5 0.12 195 20 182 63 Ic.sub.1 -3 Me Me H H.sub.2 O
EtOH 323-328 17 0.42 8 0.14 200 40 190 52 Ic.sub.1 -4 (CH.sub.2)
.sub.4 H 1/2 H.sub.2 O EtOH 343-346 18 0.335 4 0.15 195 35 206 70
Ic.sub.1 -5 n-Bu H H -- EtOH 266-270 19 0.66 10 0.20 200 40 552 96
Ic.sub.1 -6 Me H 8-Me -- CHCl .sub.3MeOH 330-333 20 0.635 7 0.22
195 60 340 62 Ic.sub.1 -7 Me H 8-MeO -- EtOH 301-302 21 0.62 10.5
0.18 200 50 467 86 Ic.sub.1 -8 Me H 8-Cl -- EtOH 328-333 22 0.64
9.6 0.19 200 50 480 86 Ic.sub.1 -9 Me H 8-F -- CHCl .sub.3MeOH
320-325 23 0.70 7 0.24 195 60 372 63 Ic.sub.1 -10 Me H 7-Me -- EtOH
322-325 24 0.60 6 0.20 195 60 331 63 Ic.sub.1 -11 Me H 7-Cl -- EtOH
320-325 25 0.517 6 0.20 195 25 319 81 Ic.sub.1 -12 H Me H -- EtOH
310-312 26 0.200 4 0.20 200 20 114 80 Ic.sub.1 -13 Cl H H H.sub.2 O
CHCl .sub.3MeOH 309-312
__________________________________________________________________________
EXAMPLE 27
(1)
2-[3-(2-Methoxycarbonylthienyl)]-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-
one Ia.sub.2 -1 ##STR18##
To a suspension of 1.04 g of ethyl
4-[3-(2-methoxycarbonylthienyl)hydrazono]-1,4-dihydroquinoline-3-carboxyla
te in 14 ml of ethanol (1.04 g) is added 3.4 ml of 1N sodium
hydroxide under nitrogen gas at room temperture. The mixture is
stirred for 10 minutes, acidified with acetic acid, and dried up
under reduced pressure. The residue is mixed with water, filtered,
washed with water, and recrystallized from ethanol to give 0.93 g
(yield: 96%) of Ia.sub.2 -1 as yellow crystals.
m.p.: 240.degree.-241.degree. C.
(2)
2-[3-(2-Carboxythienyl)]-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one
Ib.sub.2 -1 ##STR19##
To a suspension of 515 mg of
2-[3-(2-methoxycarbonylthienyl)]-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-
one Ia.sub.2 -1 in 7.5 ml of methanol is added 7.5 ml of 1N sodium
hydroxide. The mixture is stirred at 40.degree. C. for 1 hour and
cooled. The resulting mixture is mixed with acetic acid; and the
precipitating crystals are collected by filtration, washed with
water, and dried to give 452 mg of Ib.sub.2 -1 as yellowish green
crystals.
m.p.: 263-265 (d).
The compound Ib.sub.2 -1 can directly be prepared by reacting the
compound II.sub.2 -1 in the above manner.
EXAMPLES 28-37 ##STR20##
To a suspension of an ethyl
4-[3-(2-methoxycarbonylthienyl)-hydrazono]-1,4-dihydroquinoline-3-carboxyl
ate (II.sub.2) in ethanol is added 1N sodium hydroxide under
nitrogen gas at room temperature. The mixture is stirred for about
several 10 minutes to about several hours, acidified with acetic
acid, and dried up under reduced pressure. The residue is mixed
with water, filtered, washed with water, and recrystallized from an
appropriate solvent to give yellow crystalline compound (Ia.sub.2).
##STR21##
To a suspension of a
2-[3-(2-methoxycarbonylthienyl)]-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-
one (Ia.sub.2) in methanol is added 1N sodium hydroxide under
nitrogen gas. The mixture is stirred for a period of about several
10 minutes to several hours with heating. After cooling, the
reaction mixture is mixed with acetic acid; and the precipitating
crystals are collected by filtration, washed with water, and dried
to give a
2-[3-(2-carboxythienyl)]-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one
(Ib.sub.2) as yellow crystals.
The reaction conditions to prepare the compound (Ia.sub.2) from the
corresponding compound (II.sub.2), yield (g), (%), structural
formulae, recrystallization solvent, and melting point of the
compound (Ia.sub.2) are shown in Table 4; the reaction conditions
to prepare the compound (Ib.sub.2) from the corresponding compound
(Ia.sub.2), yield, structural formulae, and decomposition point of
the compound (Ib.sub.2) are shown in Table 5.
TABLE 4
__________________________________________________________________________
##STR22## Amount of Compound reaction Compound (Ia.sub.2) Ex
(II.sub.2) ethanol INNaOH time yield yield Compd. crystal
recrystalli- No. (g) (ml) (ml) (min) (g) (%) No. R.sup.1 R.sup.2 X
water zation m.p.
__________________________________________________________________________
(.degree.C.) 28 13.4 200 38 60 11.50 97 Ia.sub.2 -2 Me H H H.sub.2
O EtOH 260-261 29 0.74 8 2.2 50 0.573 88 Ia.sub.2 -3 H Me H -- EtOH
265-167d 30 0.95 19 2.6 80 0.66 79 Ia.sub.2 -4 Me H 8-Me -- MeOH
179-181d 31 1.20 70 3.8 60 1.04 98 Ia.sub.2 -5 Me H 8-MeO -- MeOH
275-277 32 0.37 15 1.0 90 0.285 87 Ia.sub.2 -6 Me H 8-Cl 1/2
H.sub.2 O EtOH 195-199 33 1.02 25 2.9 90 0.865 96 Ia.sub.2 -7 Me H
8-F H.sub.2 O MeOH 189-191d 34 0.945 50 4.7 120 0.575 69 Ia.sub.2
-8 Me H 7-Me 3/4 H.sub.2 O MeOH 153-156 35 1.45 69 6.9 90 1.04 81
Ia.sub.2 -9 Me H 7-Cl -- EtOH 167-169 36 0.66 5 1.8 60 0.55 94
Ia.sub.2 -10 Et H H -- EtOH 150-155 37 3.118 50 8.3 120 2.28 82
Ia.sub.2 -11 Me H 7-MeO -- EtOH 223-230
__________________________________________________________________________
TABLE 5
__________________________________________________________________________
##STR23## Amount of reaction Compound tempera- reaction Compound
(Ib.sub.2) Ex (Ia.sub.2) methanol INNaOH ture time yield yield
Compd. crystal dec. point No. (g) (ml) (ml) (.degree.C.) (min) (g)
(%) No. R.sup.1 R.sup.2 X water (.degree.C.)
__________________________________________________________________________
28 10.90 200 96 reflux 60 9.70 93 Ib.sub.2 -2 Me H H 1/3 H.sub.2 O
260-261 29 0.53 5 10 60 60 0.465 91 Ib.sub.2 -3 H Me H 1/4 H.sub.2
O 297-299 30 0.62 6 10 60 50 0.495 83 Ib.sub.2 -4 Me H 8-Me 2/5
321-324 O 31 0.955 15 7.8 reflux 40 0.82 90 Ib.sub.2 -5 Me H 8-MeO
-- 307-312 32 0.67 6 10 60 40 0.592 92 Ib.sub.2 -6 Me H 8-Cl 5/4
344-347 O 33 0.15 1.5 2 50 30 0.125 87 Ib.sub.2 -7 Me H 8-F H.sub.2
O 324-328 34 0.513 8 5 reflux 30 0.41 85 Ib.sub.2 -8 Me H 7-Me 1/2
H.sub.2 O 301-304 35 0.917 15 7.4 reflux 30 0.833 94 Ib.sub.2 -9 Me
H 7-Cl -- 337-340 36 0.44 8 3.7 reflux 60 0.42 98 Ib.sub.2 -10 Et H
H H.sub.2 O >300 37 4.076 66 33 reflux 80 3.72 95 Ib.sub.2 -11
Me H 7-MeO 1/3 H.sub.2 O >300
__________________________________________________________________________
EXAMPLE 38
2-(3-Thienyl)-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one Ic.sub.2
-1 ##STR24##
To a suspension of 400 mg of
2-[3-(2-carboxythienyl)]-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one
Ib.sub.2 -1 in 4 ml of quinoline is added 200 mg of copper powder.
The mixture is stirred under nitrogen gas at 195.degree. C. for 10
minutes; and copper powder is removed by filtration. The filtrate
is mixed with 1N sodium hydroxide, extracted with ether to remove
quinoline. The separated aqueous layer is filtered and the filtrate
is mixed with acetic acid. The precipitating crystals are collected
by filtration, washed with water, and recrystallized from ethanol
to give 321 mg of Ic.sub.2 -1 as yellow crystals.
m.p.: 323.degree.-325.degree. C. (d).
EXAMPLES 39-48 ##STR25##
To a suspension of the compound (Ib.sub.2) in quinoline is added
copper powder. The mixture is stirred under nitrogen gas with
heating for a period of about several 10 minutes to about several
hours. After cooling, copper powder is removed by filtration. The
filtrate is mixed with 1N sodium hydroxide and extracted with
ether. The separated aqueous layer is filtered, and the filtrate is
mixed with acetic acid. The precipitating crystals are collected by
filtration, washed with water, and recrystallized from an
appropriate solvent to give the compound (Ic.sub.2) as yellow
crystals.
The reaction conditions to prepare the compound (Ic.sub.2) from the
corresponding compound (Ib.sub.2), yield, structural formulae,
recrystallization solvent, and decomposition point of the compound
(Ic.sub.2) are shown in Table 6.
TABLE 6
__________________________________________________________________________
##STR26## Amount reaction reac- Compound (Ic.sub.2) of quino-
copper tempera- tion dec. Ex. Compound line powder ture time yield
yield Compd. crystal recrystalliza- point No. (Ib.sub.2) (g) (ml)
(g) (.degree.C.) (min) (g) (%) No. R.sup.1 R.sup.2 X water tion
(.degree.C.)
__________________________________________________________________________
39 5.00 50 1.50 190 60 3.60 85 Ic.sub.2 -2 Me H H 1/4 H.sub.2 O
EtOH 298- 300 40 0.41 8 0.12 200 30 0.33 93 Ic.sub.2 -3 H Me H 1/2
H.sub.2 O EtOH 313- 315 41 0.45 9 0.135 195 40 0.32 82 Ic.sub.2 -4
Me H 8-Me -- MeOH 330- 332 42 0.737 7.4 0.24 195 70 0.515 80
Ic.sub.2 -5 Me H 8-MeO H.sub.2 O EtOH 322- 324 43 0.43 8 0.13 195
40 0.303 81 Ic.sub.2 -6 Me H 8-Cl -- EtOHCHCl.sub.3 349- 352 44
0.54 8 0.16 200 40 0.405 86 Ic.sub.2 -7 Me H 8-F -- MeOH 326- 329
45 0.392 5 0.13 195 60 0.23 68 Ic.sub.2 -8 Me H 7-Me 3/4 H.sub.2 O
EtOH 311- 314 46 0.70 10 0.24 195 60 0.402 65 Ic.sub.2 -9 Me H 7-Cl
-- -- 323- 327 47 0.40 3 0.13 190 120 0.28 80 Ic.sub.2 -10 Et H H
1/3 H.sub.2 O EtOH 266- 268 48 3.67 33 1.13 195 110 2.80 86
Ic.sub.2 -11 Me H 7-MeO 1/4 H.sub.2 O EtOH 317- 321
__________________________________________________________________________
EXAMPLE 49 ##STR27##
2-[3-(5-Chlorothienyl)]-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one
4
(1) To a solution of 400 mg of ethyl
4-chloroquinoline-3-carboxylate 1 in 10 ml of ethanol is added 380
mg of N.sup.1 -tert-butoxycarbonyl-N.sup.1
-[3-(5-chlorothienyl)]hydrazine 2. The mixture is stirred at
40.degree. C. for 1 hour and concentrated. The resulting residue is
mixed with chloroform, washed with aqueous sodium bicarbonate and
water, dried with anhydrous magnesium sulfate, and concentrated.
The residue is purified by silica-gel column chromatography
(benzene:ethyl acetate=30:1) to give 670 mg (yield: 93%) of ethyl
4-[N.sup.2 -3-(5-chlorothienyl)-N.sup.2
-t-butoxycarbonyl]hydrazinoquinoline-3-carboxylate 3.
m.p.: 134.degree.-135.degree. C.
(2) To a solution of 600 mg of crystalline compound 3 in 15 ml of
dichloromethane is added 10 ml of trifluoroacetic acid. The mixture
is stirred at 50.degree. C. for 20 minutes and concentrated. The
resulting residue is dissolved in 30 ml of ethanol and mixed with 8
ml of 1N sodium hydroxide under ice-cooling. The reaction mixture
is stirred at room temperature for 1.5 hours and concentrated. The
residue is mixed with 10 ml of water and extracted with ether to
remove the fat-soluble portion. The aqueous layer is filtered; and
the filtrate is mixed with acetic acid. The precipitating solid is
collected by filtration and recrystallized from ethanol to give 210
mg of
2-[3-(5-chlorothienyl)]-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one
4.
Yield: 52%.
m.p.: 287.degree.-289.degree. C.
NMR(DMSO-d.sub.6): 7.45-7.82(5H, m);, 8.17-8.27(1H, m), 8.75(1H,
s).
Anal. Calcd. (%) (for C.sub.14 H.sub.8 N.sub.3 OSCl): C, 55.73; H,
2.68; N, 13.93. Found (%): C, 55.56; H, 2.99; N, 13.56.
The reagent N.sup.1 -tert-butoxycarbonyl-N.sup.1
-[3-(5-chlorothienyl)]hydrazine 2 is prepared by subjecting
3-tert-butoxycarbonylamino-5-chlorothiophene (m.p.:
86.degree.-87.degree. C.) to the amination according to Synthesis,
487, 1977; and the latter is prepared from
5-chlorothiophene-3-carboxylic acid in the manner discribed as in
Synthesis, 255, 1977.
EXAMPLE 50 ##STR28##
(1)
2-[2-(5-Ethoxycarbonylthienyl)]-2,5-dihydro-3H-pyrazolo[4,3-c]-quinolin-3-
one 6
To a solution of 942 mg of ethyl 4-chloroquinoline-3-carboxylate 1
in 10 ml of ethanol is added 981 mg of ethyl
5-hydrazinothiophene-2-carboxylate 5 [Can. J. Chem., 44, 2881
(1966), m.p.: 160.degree.-170.degree. C.]. The mixture is stirred
at 50.degree.-55.degree. C. for 30 minutes and concentrated. The
resulting mixture is mixed with sodium bicarbonate, extracted with
chloroform, washed with water, dried, and evaporated. The residue
is purified by silica-gel column chromatography to give 645 mg
(48%) of the titled compound 6 as crystals. m.p.: higher than
300.degree. C.
NMR(DMSO-d.sub.6) .delta.: 1.31(3H, t), 4.29(2H, q), 7.38(1H, d),
7.50-7.89 (4H, m), 8.19-8.30(1H, m), 8.88(1H, s).
(2) 2-(2-Thienyl)-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one
7
To a suspension of 340 mg of the compound 6 in 5 ml of methanol is
added 5 ml of 1N sodium hydroxide. The mixture is stirred at
50.degree.-55.degree. C. for 30 minutes. After cooling, the mixture
is mixed with 4 ml of 1N hydrochloric acid, and 0.5 ml of acetic
acid. The precipitating crystals are collected by filtration,
washed with water, and dried. The mixture of 280 mg of
2-[2-(5-carboxythienyl)]-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one,
3 ml of quinoline, and 140 mg of copper powder is heated at
190.degree. C. under nitrogen gas for 20 minutes and cooled. After
the removal of copper powder, the mixture is shaken with ether and
1N sodium hydroxide. The aqueous layer is separated and acetic acid
is added thereto. The precipitating crystals are collected by
filtration to give 210 mg (74%) of crystalline compound 7 as
monohydrate.
m.p.: higher than 300.degree. C.
NMR(DMSOd.sub.6).delta.:6.92-7.14(2H, m), 7.37(1H, dd),
7.50-7.75(3H, m), 8.16-8.27(1H, m), 8.77(1H, s).
EXAMPLE 51 ##STR29##
(1)
2-[2-(5-Ethoxycarbonylthienyl)]-8-fluoro-2,5-dihydro-3H-pyrazolo[4.3-c]-qu
inolin-3-one 9
A mixture of 1.27 g of ethyl
4-chloro-6-fluoroquinoline-3-carboxylate 8 and 1.11 g of ethyl
5-hydrazinothiophene-2-carboxylate 5 is stirred at 40.degree. C. in
50 ml of ethanol for 1 hour. The mixture is treated in the same
manner as in Example 50 to give 805 mg (45%) of the title compound
9 as crystals.
m.p.: higher than 300.degree. l C.
NMR(DMSOd.sub.6) .delta.: 1.31(3H, t), 4.28(2H, q), 7.37(1H, d),
7.48-7.96 (4H, m), 8.88(1H, s).
(2)
2-(2-Thienyl)-8-fluoro-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one
10
A solution of 1.10 g of the compound 9 in 22 ml of methanol and 11
ml of 1N sodium hydroxide is heated at 60.degree. C. for 1 hour,
neutralized with hydrochloric acid, and acidified with acetic acid.
The resulting crystals are collected by filtration to give a
carboxylic acid. The mixture of the carboxylic acid and 270 mg of
copper powder in 14 ml of quinoline is heated at 200.degree. C. for
50 minutes. After removal of copper powder, the mixture is shaken
with ether and 1N sodium hydroxide. The aqueous layer is separated
and mixed with acetic acid. The precipitating crystals are
collected by filtration and purified by silica-gel column
chromatography to give 370 mg (48%) of the compound 10.
m.p.: higher than 300.degree. C.
NMR(DMSOd.sub.6) .delta.: 6.92-7.16(2H, m), 7.38(1H, dd),
7.50-7.97(3H, m), 8.82(1H, s).
(3)
2-[2-(3,5-Dibromothienyl)]-8-fluoro-2,5-dihydro-3H-pyrazolo[4,3-c]-quinoli
ne-3-one 11
A mixture of 330 mg of the compound 10and 495 mg of
N-bromosuccinimide in carbon tetrachloride is refluxed for 3.5
hours. The reaction mixture is extracted with aqueous sodium
hydroxide; and the aqueous layer is neutralized with hydrochloric
acid and acidified with acetic acid. The precipitating crystals are
collected by filtration and purified by silica-gel column
chromatography to give 315 mg (62%) of the compound 11 as
crystals.
m.p.: 277.degree.-281.degree. C. (d).
NMR(DMSOd.sub.6) .delta.: 7.34(1H, s), 7.53-7.89(3H, m), 8.77(1H,
s).
EXAMPLE 52 ##STR30##
2-[3-(2-Chloro-5-methylthienyl)]-2,5-dihydro-3H-pyrazolo[4,3-c]-quinolin-3-
one 12
To a suspension of 110 mg of
2-[3-(5-methylthienyl)]-2,5-dihydro-3H-pyrazolo[4,3-c]quinoline-3-one
Ic.sub.2 -2 in 1 ml chloroform is added 0.42 ml of a solution of
(1.3M) chlorine in carbon tetrachloride. The mixture is stirred at
room temperature for 2 hours. The precipitating crystals are
collected by filtration, dissolved in 1N sodium hydroxide, and
mixed with acetic acid. The precipitating crystals are collected by
filtration to give 77 mg (60%) of the compound 12 as crystals (3/4
mole hydrate).
m.p.: 156.degree.-160.degree. C.
NMR(DMSOd.sub.6) .delta.: 2.44(3H, s), 6.99-7.03(1H, m),
7.40-8.18(4H, m), 8.70(1H, s).
EXAMPLE 53 ##STR31##
2-[3-(2-Bromo-5-methylthienyl)]-2,5-dihydro-3H-pyrazolo[4,3-c]quinoline-3-o
ne 13
To a suspension of 196 mg of
2-[3-(5-methylthienyl)]-2,5-dihydro-3H-pyrazolo[4,3-c]quinoline-3-one
Ic.sub.2 -2 in 5 ml of chloroform is dropwise added a solution of
160 mg of bromine in 2 ml of chloroform at room temperature, The
mixture is stirred at room temperature for 2 hours. The
precipitating crystals are collected by filtration to give 190 mg
of the compound 13 as dihydrate.
Yield: 63%.
m.p.: 238.degree.-243.degree. C. (d).
NMR(DMSOd.sub.6) .delta.: 2.44(3H, s), 6.93-6.97(1H, m),
7.40-7.75(3H, m), 8.05-8.17(1H, m), 8.68(1H, s).
EXAMPLE 54 ##STR32##
5-Methyl-2-[2-(5-methylthienyl)]-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-o
ne 14
To a suspension of 400 mg of
2-[2-(5-methylthienyl)]-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one
Ic.sub.1 -1 in 10 ml of anhydrous tetrahydrofuran is added 60 mg of
60% sodium hydride (in mineral oil) under nitrogen gas. The mixture
is refluxed for 1.5 hours and mixed with a solution of 283 mg of
methyl iodide in 0.5 ml of anhydrous tetrahydrofuran with
ice-cooling under stirring. The mixture is stirred at room
temperature for 3 hours.
The precipitating crystals are collected by filtration and washed
with a mixture of ethanol and ether. The resulting crystals are
recrystallized from chloroform-methanol to give 355 mg of the
compound 14 as crystals.
m.p.: 271.degree.-274.degree. C. (d).
Anal. Calcd. (%) (for C.sub.16 H.sub.13 N.sub.3 OS.1/8H.sub.2 O):
C, 64.57; H, 4.49; N, 14.12. Found (%): C, 64.45; H, 4.65; N,
14.14.
NMR(in DMSO-d.sub.6) .delta.: 2.40(3H, d), 4.02(3H, s), 6.63 (1H,
dd), 7.11(1H, d), 7.50-8.32(4H, m), 8.87(1H, s)ppm.
EXAMPLE 55 ##STR33##
5-Acetyl-2-[2-(5-methylthienyl)]-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-o
ne 15
To a suspension of 562 mg of
2-[2-(5-methylthienyl)]-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one
Ic.sub.1 -1 in 10 ml of anhydrous tetrahydrofuran is added 60 mg of
60% sodium hydride (in mineral oil) under nitrogen gas. The mixture
is refluxed for 2 hours and mixed with a solution of 196 mg of
acetyl chloride in 1 ml of anhydrous tetrahydrofuran under
ice-cooling. The mixture is stirred at room temperature for 2
hours; and 0.1 ml of acetic acid is added thereto. The
precipitating crystals are collected by filtration, washed with
ether-tetrahydrofuran and water, and dried to give 520 mg of the
compound 15 as crystals.
m.p.: 306.degree.-309.degree. C.(d).
Anal. Calcd. (%) (for C.sub.17 H.sub.13 N.sub.3 O.sub.2
S.1/5H.sub.2 O): C, 62.45; H, 4.14; N, 12.85. Found (%): C, 62.71;
H, 4.42; N, 12.56.
NMR(DMSOd.sub.6) .delta.: 2.43(3H, s), 2.89(3H, s), 6.67(1H, dd),
7.12(1H, dd), 7.50-8.38(4H, m), 9.00(1H, s)ppm.
EXAMPLE 56
A mixture of 281 mg of
2-[2-(5-methylthienyl)]-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one
Ic.sub.1 -1, 5 ml of trifluoroacetic acid, and 96 mg of
methanesulfonic acid is stirred at room temperature for 1.5 hours
and dried up under reduced pressure. The resulting residue is mixed
with ethyl ether and collected by filtration to give 300 mg (yield:
80%) of the compound Ic.sub.1 -1as methanesulfonate.
m.p.: 230.degree.-234.degree. C.(d).
Anal. Calcd. (%) (for C.sub.16 H.sub.15 N.sub.3 O.sub.4
S.sub.2.1/2H.sub.2 O): C, 49.72; H, 4.17; N, 10.87. Found (%): C,
49.72; H, 4.16; N, 10.88.
EXAMPLE 57
A mixture of 281 mg of
2-[2-(5-methylthienyl)]-2,5-dihydro-3H-pyrazolo[4,3-c]quinoline-3-one
Ic.sub.1 -1 in 2 ml of 0.5N sodium hydroxide is stirred for 24
hours. The reaction mixture is filtered, and the filtrate is dried
up under reduced pressure. The resulting residue is washed with
ether-ethanol and dried to give 185 mg (yield: 31%) of sodium salt
of the compound Ic.sub.1 -1.
m.p.: 273.degree.-277.degree. C.(d).
Anal. Calcd. (%) (for C.sub.15 H.sub.10 N.sub.3 OSNa): C, 59.40; H,
3.32; N, 13.85. Found (%): C, 59.68; H, 3.70; N, 13.87.
EXAMPLE 58
2-{2-[5-chloro-3,4-bis(ethoxycarbonyl)thienyl]}-2,5-dihydro-3H-pyrazolo[4,3
-c]quinolin-3-one Ia.sub.1 -13' ##STR34##
To a suspension of 617 mg of
2-{-2-[3,4-bis(ethoxycarbonyl)thienyl]}-2,5-dihydro-3H-pyrazolo[4,3-c]quin
oline-3-one Ia.sub.1 -13 in 20 ml of chloroform is dropwise added
1.4 ml of a solution of 1.35M chlorine in carbon tetrachloride at
0.degree.-5.degree. C. The mixture is stirred at
10.degree.-15.degree. C. for 40 minutes and filtered; and the
filtrate is concentrated. The residue is dissolved in ether and
shaken with aqueous sodium hydroxide. The separated aqueous layer
is neutralized with acetic acid and the precipitating crystals are
collected by filtration to give 289 mg (43%) of the compound
Ia.sub.1 -13' as yellow crystals. Ia.sub.1 -13' was utilized to
prepare Ib.sub.1 -13 in Example 13.
m.p.: 152.degree.-155.degree. C. (d).
EXAMPLE 59
2-[3-(5-Methyl-2-methoxycarbonylthienyl)]-2,5-dihydro-3H-imidazo[4,3-c]cinn
olin-3-one A ##STR35##
A solution of 500 mg of methyl 4-chlorocinnoline-3-carboxylate and
460 mg of methyl 5-methyl-3-hydrazinothiophene-2-carboxylate in 7
ml of ethanol is stirred at room temperature for 30 minutes. The
mixture is concentrated and mixed with aqueous ammonia, and
precipitating crystals are filtered and dried. This is stirred in a
mixture of methanol (6 ml)-1N sodium hydroxide (1.2 ml) at room
temperature for 1 hour and acidified with acetic acid. The
resulting crystals are filtered, washed with water, and dried to
give 640 mg (86%) of the compound A as crystals. This is
recrystallized from ethanol to give strong red crystals.
m.p.: 295.degree.-300.degree. C.
EXAMPLE 60
2-[3-(5-Methylthienyl)]-2,5-dihydro-3H-imidazo[4,3-c]cinnolin-3-one
B ##STR36##
To a suspension of 330 mg of
2-[3-(5-methyl-2-methoxycarbonylthienyl)]-2,5-dihydro-3H-imidazo[4,3-c]cin
nolin-3-one A in 3 ml of ethanol is added 3 ml of 1N sodium
hydroxide. The mixture is refluxed for 1.5 hours, cooled and
acidified with acetic acid. The precipitating crystals are filtered
and dried. These crystals are suspended in 2.5 ml of quinoline and
95 mg of copper powder and heated at 195.degree. C. for 45 minutes.
After removal of copper powder, the mixture is shaken with 3 ml of
1N sodium hydroxide and ether. The separated aqueous layer is
filtered by passing through celite. The filtrate is mixed with
acetic acid to give 190 mg (74%) of the compound B as strong red
crystals.
m.p.: >310.degree. C.
EXAMPLE 61
2-[2-(5-Methyl-3-methoxycarbonylthienyl)]-2,5-dihydro-3H-pyrazolo[4,3-c]cin
nolin-3-one C
A solution of 480 mg of 4-chlorocinnoline-3-carboxylic acid and 441
mg of methyl 5-methyl-2-hydrazinothiophene-2-carboxylate in 6 ml of
ethanol is stirred at room temperature for 30 minutes. The reaction
mixture is concentrated and mixed with aqueous ammonia; and the
precipitating crystals are filtered and dried. This is added to the
mixture of 10 ml of methanol and 1.9 ml of 1N sodium hydroxide. The
mixture is stirred at room temperature for 1 hour and acidified
with acetic acid. The resulting crystals are filtered, washed with
water, and dried to give 540 mg (73%) of the compound C as strong
red crystals.
m.p.: 138.degree.-140.degree. C.
EXAMPLE 62
2-[2-(5-Methylthienyl)]-2,5-dihydro-3H-pyrazolo[4,3-c]cinnolin-3-one
D ##STR37##
To a suspension of 420 mg of
2-[2-(5-methyl-3-methoxycarbonyl)thienyl]-2,5-dihydro-3H-pyrazolo[4,3-c]ci
nnolin-3-one C in 8 ml of ethanol is added 4 ml of sodium
hydroxide. The mixture is refluxed for 1 hour, cooled, and
acidified with acetic acid. The precipitating crystals are filtered
and dried. The crystals are suspended in 3 ml of quinoline and 130
mg of copper powder. The suspension is heated at 195.degree. C. for
1 hour. After removal of copper powder, the mixture is shaken with
4 ml of 1N sodium hydroxide. The separated aqueous layer is
filtered through celite. The filtrate is mixed with acetic acid and
the precipitating crystals are collected by filtration to give 200
mg (72%) of the compound D as strong red crystals.
m.p.: >310.degree. C.
EXAMPLES 63-64 ##STR38##
2-[3-(5-Methylthienyl)]-8-hydroxy-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-
one E, (Example 63)
1.066 g of
2-[3-(5-methylthienyl)]-8-methoxy-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3
-one Ic.sub.2 -5 is dissolved in 33 ml of quinoline with heating.
After cooling, the mixture is mixed with 3 ml of trimethylsilyl
iodide and stirred at 190.degree. C. for 2 hours. The reaction
mixture is mixed with 40 ml of 2N hydrochloric acid, stirred for
several hours, basified with 2N sodium hydroxide, and extracted
with ether to remove quinoline. The aqueous layer is decolorized
with active carbon and mixed with acetic acid. The precipitating
crystals are collected by filtration and purified by silica-gel
column chromatography. The fractions eluted by chloroform-methanol
(50:3) are recrystallized from chloroform-methanol to give 797 mg
(89%) of the compound E.sub.1 as yellow crystals.
m.p.: >300.degree. C.
Anal. Calcd. (%) (for C.sub.15 H.sub.11 N.sub.3 O.sub.2 S.CH.sub.3
OH): C,58.34; H,4.59; N,12.75; S,9.73. Found (%): C,58.14; H,4.42;
N,12.84; S,9.19.
2-[3-(5-Methylthienyl)]-7-hydroxy-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-
one E.sub.2 (Example 64)
A mixture of 783 mg of
2-[3-(5-methylthienyl)]-7-methoxy-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3
-one Ic.sub.2 -11, 25 ml of quinoline, and 2.5 ml of trimethylsilyl
iodide is treated in the same manner as in Example 63 to give 389
mg (52%) of the compound E.sub.2 as yellow crystals.
m.p.: 312.degree.-318.degree. C.
Anal. Calcd. (%) (for C.sub.15 H.sub.11 N.sub.3 O.sub.2
S.4/5H.sub.2 O): C,57.79; H,4.07; N,13,48; S,10.29. Found (%):
C,57.75; H, 4.28;N,13.41; S,9.95.
EXAMPLES 65-67
5-Alkyl-2-[3-(5-methylthienyl)]-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-on
e F ##STR39##
To a suspension of 1562 mg of
2-[3-(5-methylthienyl)]-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one
Ic.sub.2 -2 in 5 ml of anhydrous tetrahydrofuran is added 88 mg of
60% sodium hydride (in mineral oil). The mixture is refluxed for 2
hours and cooled. The mixture is mixed with alkyl iodide, stirred
over night, and mixed with water. The precipitating crystals are
filtered, washed with water, and with ethanol, and dried to give
the compound F as yellow crystals.
Compounds provided are shown in the following Table.
______________________________________ amount of yield yield R RI
(mg) (mg) (%) m.p. (.degree.C.)
______________________________________ Me 300 452 76 253-258 (d) Et
600 390 65 216-218 (d) n-Bu 736 421 62 233-235 (d)
______________________________________
EXAMPLE 68
5-Methanesulfonyl-2-[3-(5-methylthienyl)]-2,5-dihydro-3H-pyrazolo[4,3-c]qui
nolin-3-one G ##STR40##
To a suspension of 2.86 g of
2-[3-(5-methylthienyl)]-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one
Ic.sub.2 -2 in 60 ml of anhydrous tetrahydrofuran is added 313 mg
of 60% sodium hydride (mineral oil). The mixture is refluxed for 1
hour, cooled to 6.degree. C., and to this mixture is dropwise added
a solution of 1.26 g of methanesulfonyl chloride in 20 ml of
anhydrous tetrahydrofuran. The mixture is stirred for 3.5 hours,
concentrated under reduced pressure, mixed with water, and
acicified with acetic acid. The precipitating material is collected
by filtration, washed with water, dried, and recrystallized from
chloroform-methanol to give 2.44 g (68%) of the orange crystalline
compound G.
m.p.: 179.degree.-182.degree. C. (d).
Anal. Calcd. (%) (for C.sub.16 H.sub.13 N.sub.3 O.sub.3 S.sub.2):
C,53.46; H,3.64; N,11.69; S,17.84. Found (%): C,53.31; H,3.85;
N,11.56; S,17.43.
REFERENTIAL EXAMPLE 1 ##STR41##
Ethyl
4-[2-(3-ethoxycarbonyl-5-methylthienyl)hydrazono]-1,4-dihydroquinoline-3-c
arboxylate II.sub.1 -1
To a solution of 942 mg of ethyl 4-chloroquinoline-3-carboxylate 1
in 10 ml of ethanol is added 880 mg of ethyl
2-hydrazino-5-methylthiophene-3-carboxylate 16. The mixture is
stirred at room temperature for 1 hour and evaporated. The
resulting residue is dissolved in chloroform and washed with cooled
aqueous sodium bicarbonate and with water. The solution is dried
over anhydrous magnesium sulfate and evaporated. The resulting
solid is recrystallized from ethanol to give 1.47 g (yield: 92%) of
the compound II.sub.1 -1 as orange crystals.
m.p.: 173.degree.-174.degree. C.
REFERENTIAL EXAMPLES 2-13 ##STR42##
To a solution of an ethyl 4-chloroquinoline-3-carboxylate (III) in
ethanol is added a 2-hydrazinothiophene-3-carboxylic acid ester
(IV.sub.1). The mixture is stirred at room temperature for 1 hour
and evaporated. The resulting residue is dissolved in chloroform
and washed with cold aqueous sodium bicarbonate and with water. The
solution is dried over anhydrous magnesium sulfate and evaporated.
The resulting solid is recrystallized from an appropriate solvent
to give the compound (II.sub.1) as orange crystals.
The reaction conditions to prepare the compound (II.sub.1) from the
compound (III) and the compound (IV.sub.1) and physical properties
of the resulting compound (II.sub.1) are shown in Table 7.
TABLE 7
__________________________________________________________________________
##STR43## Reaction Reac- Ref. Amount (mg) Eth- tempera- tion
Compound (II.sub.1) Ex. Compd. Compd. anol ture time Yield Compd.
No. (III) (IV.sub.1) (ml) (.degree.C.) (hrs) (g) (%) No. R.sup.1
R.sup.2 R X R.S. m.p.
__________________________________________________________________________
(.degree.C.) 2 707 770 7 reflux 1 1.10 89 II.sub.1 -2 Et H Et H
EtOH 156-158 3 790 790 20 40 1 1.38 69 II.sub.1 -3 Me Me Et H "
161-164 4 838 940 20 " 1 0.63 57 II.sub.1 -4 (CH.sub.2).sub.4 Et H
" 176-177 5 1500 1600 15 reflux 0.5 2.55 91 II.sub.1 -5 n-Bu H Me H
" 173-175 6 749 614 15 " 1 1.11 93 II.sub.1 -6 Me H Me 6-Me "
180-182 7 930 720 14 " 1.5 1.27 88 II.sub.1 -7 Me H Me 6-MeO "
164-165 8 810 614 25 " 1.5 1.09 87 II.sub.1 -8 Me H Me 6-Cl "
196-197 9 750 653 20 " 1.5 1.05 88 II.sub.1 -9 Me H Me 6-F " 184-
186 10 600 500 10 " 1 0.80 83 II.sub.1 -10 Me H Me 7-Me EtOH
169-170 hexane 11 1350 1030 23 " 1 1.83 88 II.sub.1 -11 Me H Me
7-Cl EtOH 186-187 hexane 12 707 899 20 50 0.5 1.29 91 II.sub.1 -12
COOEt Me Et H EtOH 221-224(d) 13 1330 1530 30 r.t. 0.9 2.34 91
II.sub.1 -13 H COOEt Et H " 178-181(d)
__________________________________________________________________________
*r.t.: room temperature **R.S.: recrystallization solvent
REFERENTIAL EXAMPLE 14 ##STR44##
Ethyl
4-[3-(2-methoxycarbonylthienyl)hydrazono]-1,4-dihydroquinoline-3-carboxyla
te II.sub.2 -1
To a solution of 942 mg of ethyl 4-chloroquinoline-3-carboxylate 1
in 8 ml of wethanol is added 758 mg of methyl
3-hydrazinothiophene-2-carboxylate 17. The mixture is stirred at
room temperature for 1 hour and dried up under reduced pressure.
The residue is dissolved in chloroform and washed with cold aqueous
sodium bicarbonate and with water. The solution is dried and
evaporated to give a solid. This is recrystallized from ethanol to
give 1.46 g of the compound II.sub.2 -1 as pale yellowish
crystals.
m.p.: 161.degree.-162.degree. C.
REFERENTIAL EXAMPLES 15-23 ##STR45##
To a solution of an ethyl 4-chloroquinoline-3-carboxylate (III) in
ethanol is added a 3-hydrazinothiophene-2-carboxylic acid ester
(IV.sub.2). The mixture is stirred at room temperature for 1 hour
and evaporated. The reslting residue is dissolved in chloroform and
washed with cooled aqueous sodium bicarbonate and with water. The
solution is dried over anhydrous magnesium sulfate and evaporated.
The resulting solid is recrystallized from an appropriate solvent
to give the compound (II.sub.2) as crystals.
The reaction conditions to prepare the compound (II.sub.2) from the
compound (III) and the compound (IV.sub.2), physical properties
(m.p., appearance) of the resulting compound (II.sub.2) are shown
in Table 8.
TABLE 8
__________________________________________________________________________
##STR46## Reaction Reac- Ref. Amount (g) temper- tion Compound
(II.sub.2) Ex. Compd. Compd. Ethanol ature time Yield Compd.
Appear- m.p. No. (III) (IV.sub.2) (ml) (.degree.C.) (hrs) (g) (%)
No. R.sup.1 R.sup.2 X R.S. ance (.degree.C.)
__________________________________________________________________________
15 8.20 7.12 80 r.t. 1 12.90 96 II.sub.2 -2 Me H H EtOH pale
200-201 yellow 16 0.471 0.39 10 40 1 0.738 96 II.sub.2 -3 H Me H "
yellow 188-191 17 0.749 0.614 23 r.t. 1 1.08 90 II.sub.2 -4 Me H
6-Me " " 197-200 18 0.93 0.716 15 " 1 1.28 88 II.sub.2 -5 Me H
6-MeO " " 167-168 19 0.450 0.343 10 40 0.7 0.642 92 II.sub.2 -6 Me
H 6-Cl " pale 222-223 yellow 20 0.75 0.653 25 r.t. 1 1.14 93
II.sub.2 -7 Me H 6-F " pale 198-201 yellow 21 0.87 0.722 15 " 1
1.22 88 II.sub.2 -8 Me H 7-Me " pale 176-178 yellow 22 1.08 0.82 20
" 1 1.59 95 II.sub.2 -9 Me H 7-Cl " yellow 198-199 23 0.50 0.445 5
" 1 0.71 84 II.sub.2 -10 Et H H " red 166-168
__________________________________________________________________________
*r.t.: room temperature **R.S.: recrystallization solvent
REFERENTIAL EXAMPLE 24 ##STR47##
Diethyl 2-hydrazinothiophene-3,4-dicarboxylate H
To a solution of 14.3 g of ethyl mercaptopyruvate in 60 ml of
ethanol is added 11.5 g of ethyl cyanoacetate at 5.degree. C. The
mixture is mixed with 0.7 ml of piperidine, stirred at room
temperature for 50 minutes, and evaporated. The residue is
dissolved in ethyl acetate, washed with water, and evaporated. The
resulting residue is crystallized from ether-hexane to give 20.2 g
(86%) of diethyl 2-aminothiophene-3,4-carboxylate as crystals,
melting at 115.degree.-118.degree. C.
To a mixture of the crystals (4.86 g) and 30 ml of conc.
hydrochloric acid is dropwise added 15 ml of an aqueous solution of
1.52 g of sodium nitrite at -10.degree..about.5.degree. C.; and the
mixture is stirred at 15.degree. C. for 30 minutes to give a
solution of diazonium salt. A solution of 26 g of stannous chloride
in 40 ml of conc. hydrocloric acid is cooled below 5.degree. C. in
an another flask, and the solution of the diazonium salt is added
thereto with stirring. The mixture is stirred at
0.degree.-5.degree. C. for 30 minutes; and the precipitating
crystals are collected by filtration and washed with ether. The
crystals are mixed with ethyl acetate, basified with 2N sodium
hydroxide, and extracted with ethyl acetate. The extract is washed
with water, dried, and evaporated. The resulting residue is
purified by silica-gel column chromatography and the fractions
eluted with methylene chloride are concentrated to give 1.96 g
(38%) of the compound H as crystals.
m.p.: 53.5.degree.-55.degree. C.
Preparation
2-[3-(5-Chlorothienyl)]-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one:
100 mg
wheat starch: 48 mg
magnesium stearate: 2 mg
The above components are mixed with each other to prepare a
capsule.
Effect of the Invention
The compounds of the present invention show high affinity to a
benzodiazepine receptor. The drugs bound to this receptor are
classified as three groups according to the difference of the
efficacy. Thus, agonists can be utilized as minor tranquilizers or
anti-convulsants, antagonists can be agents for treating
benzodiazepine intoxication and accidental supernumerary uptake,
inverse agonists are expected as vigilance enhancing compounds.
Experiments for assessing biological activities of the compounds of
the present invention are shown below; the number of the test
compound corresponds to the number used in Examples and Tables
respectively.
Experiment 1
Binding test to benzodiazepine receptor
This test was carried out in the modified method of Moeler &
Okada, Science, 198, 849-851 (1977).
Receptor preparation was provided from the cerebral cortex of
Wistar rats (male, 11 to 13 weeks age). Inhibitory action of the
test compound on the specific binding of tritium labeled diazepam
to the receptor was evaluated as follows. 2 nM tritium labeled
diazepam and an aqueous solution of the test compound at 5 or 6
concentrations were incubated with the receptor preparation at
0.degree. C. for 60 minutes. The 50% inhibitory concentration
(IC.sub.50) was measured by the concentration-response curve.
The inhibitory constant (Ki) was calculated according to the
following equation, in which Kd is the dissociation constant of the
tritium labeled diazepam and L is the concentration of the labeled
ligand. ##EQU1##
The results are shown in the following table.
______________________________________ Compd. Ki Compd. Ki No. (nM)
No. (nM) ______________________________________ Ic.sub.1 -1 0.35
Ic.sub.2 -1 0.29 Ic.sub.1 -2 1.51 Ic.sub.2 -2 0.45 Ic.sub.1 -3 0.63
Ic.sub.2 -4 0.30 Ic.sub.1 -5 1.53 Ic.sub.2 -5 0.39 Ic.sub.1 -6 0.22
Ic.sub.2 -6 0.58 Ic.sub.1 -7 0.17 Ic.sub.2 -7 0.17 Ic.sub.1 -8 0.31
Ic.sub.2 -8 1.24 Ic.sub.1 -9 0.14 Ic.sub.2 -9 0.96 Ic.sub.1 -10
1.44 Ic.sub.1 -11 1.11 Ic.sub.1 -12 0.38
______________________________________
Experiment 2
Inverse agonist activity was evaluated by the following
procedure.
The test compound was administered orally to 8-16 male mice a
group, 1 hour before a subcutaneous administration of 75 mg/kg of
pentylenetetrazol (a subconvulsive dose). The dose (ED.sub.50) at
which 50% of mice died, was calculated by the Probit method.
______________________________________ Compd. No. ED.sub.50 (mg/kg)
Note ______________________________________ Ic.sub.2 -2 1.67
Subject matter of the invention Control 1 >200.0 JP Unexamd.
Pat. Pub. No. 56-18980 Control 2 87.02 JP Unexamd. Pat. Pub. No.
59-110694 ______________________________________ Control 1: Control
2: 2(2-Thiazolyl)-2,5-dihydro-3H--pyrazolo[4,3oquinolin-3-one-
* * * * *